1. Field of Invention
This invention is directed to substituted hydrindanes and their use in preventing and treating angiogenesis-dependent diseases in warm blooded animals.
2. Description of Related Art
Angiogenesis refers to the generation and growth of new blood vessels and is often referred to as neovascularization. A number of compounds have been shown to inhibit angiogenesis. PF4 and its derivatives (Maione, et al., "Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides," Science, 247:77-79, 5 Jan. 1990), inhibitors of collagen synthesis (Ingber & Folkman, "Inhibition of Angiogenesis through modulation of collagen metabolism," Laboratory Investigation, 59:44-51, 1988), synthetic analogs of fumagillin (Ingber, et al., "Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumor growth," Nature, Vol. 348:555-557, 6 Dec. 1990), retinoids (Oikawa, et al., "A highly potent antiangiogenic activity of retinoids," Cancer Letters, 48:157-162, 1989), herbimycin A (Oikawa, et al., "Powerful antiangiogenic activity of herbimycin A," The Journal of Antibiotics, XLII:1202-1204, July, 1989), vitamin D analogs including calcitriol (Oikawa, et al, "Inhibition of angiogenesis by vitamin D.sub.3 analogues," European J. Pharmacology, 178:247-250, 1990), and angiostatic steroids in the presence of a heparin cofactor (Crum, et al., "A new class of steroids which inhibits angiogenesis in the presence of heparin or a heparin fragment," Science, 230:375-378, 20 Dec. 1985) have been demonstrated to inhibit angiogenesis in the chick embryo chorioallantoic membrane (CAM) model of neovascularization. Topical ocular administration of angiostatic steroids in a cyclodextrin formulation inhibits lipopolysaccharide induced corneal neovascularization in the rabbit (Li, et al., "Angiostatic steroids potentiated by sulphated cyclodextrin inhibit corneal neovascularization," Investigative Ophthalmology and Visual Science, 32:2898-2905, October, 1991).